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  • Our data also showed that non significant differences


    Our data also showed that non-significant differences in survival were observed among patients without driver mutations between periods B and D. This finding suggests that the approval of multiple CAs during the previous two decades may not be responsible for the improvement in the survival of patients without driver mutations. Although the follow-up time was short, we found that the survival of patients diagnosed in period E tended to be longer than that of patients diagnosed in other periods. Nivolumab, the first ICI, was approved in 2015 for the treatment of previously treated NSCLC patients. The approval of nivolumab provided a new treatment option for patients with advanced NSCLC. In a prospective phase III trial, treatment with nivolumab showed a significantly longer survival compared with docetaxel [11], [12]. The findings of the present study are consistent with those of previous trials, suggesting that the approval of nivolumab may be responsible for the prolonged OS observed in patients with advanced NSCLC without driver mutations. In 2016 and 2017, pembrolizumab and atezolizumab, respectively, were also approved in Japan. Use of these agents may contribute further to the extension of patient survival.
    Conflict of interest
    Introduction Activating mutations of the Epidermal Growth Factor Receptor () gene are found in approximately 10–12% of Caucasian patients affected by non small-cell lung cancer (NSCLC), with higher prevalence in adenocarcinoma Veratridine histology, never smokers and females [1]. Exon 19 deletions and Veratridine 21 L858R point mutation represent about 90% of these activating alterations [2]. For many years, first- (gefitinib and erlotinib) or second-generation (afatinib) EGFR-tyrosine kinase inhibitors (TKIs) have been considered the standard first-line therapy for patients with advanced EGFR-mutated NSCLC, based on the excellent outcome in comparison with standard chemotherapy [1]. Nevertheless, resistance inevitably develops and, in approximately 50% of patients, it is due to the appearance of the secondary mutation T790M in exon 20 [3]. Osimertinib is a third-generation EGFR-TKI specifically designed to target T790M-positive EGFR in patients who have developed resistance to earlier generation drugs [4]. Osimertinib significantly improves clinical outcome in these patients with respect to chemotherapy [5], but, again, resistance may develop and includes additional EGFR mutations (mainly C797S), KRAS, PIK3CA and BRAF V600E mutations, MET and HER-2 amplifications, oncogenic fusions in FGFR3, RET and NTRK and small-cell transformation [[6], [7], [8]]. Conventionally, a tissue biopsy should be performed to evaluate acquired resistance mechanisms [1]; however, re-biopsy has several limitations, considering that is an invasive procedure, not always feasible and accepted by patients, and that it does not account for the heterogeneity in resistance mechanism expressed at different tumour sites in the same patient. The use of circulating cell-free DNA (cfDNA) extracted from plasma to detect genetic alterations, also known as liquid biopsy, represents a non-invasive option and may be used to detect mechanisms of resistance to EGFR-TKIs avoiding tissue re-biopsy. Moreover, molecular analysis of plasma collected during the course of the disease allows on-treatment monitoring of disease response. To date, if a liquid biopsy is performed to detect the T790M, there is no way to demonstrate a sure predictive role about osimertinib treatment outcome. Preliminary results published by our group showed that the allele frequency (AF) of and T790M/ ratio are potential markers of outcome in patients treated with osimertinib [9]; in particular, patients who achieved a clinical benefit presented a lower AF and a higher T790M/ ratio at baseline compared to non-responders. Similarly, a significant correlation has been demonstrated on baseline plasma samples (shedders vs. non-shedders) and outcome measures of patients treated with osimertinib [10].